Microparticle drug carriers including liposomal formulations as typical examples and polypeptides such as protein drug are known to have poor retention in blood and be easily captured by the reticuloendothelial system (hereinafter abbreviated as “RES”) such as liver and spleen when they are intravenously administered. The presence of RES is a serious obstacle when a microparticle drug carrier is utilized as a targeting type preparation, which delivers a medicament to organs other than RES, and as a sustained-release preparation, which allows a medicament retained in blood for a long period of time to control the release of the medicament.
Researches have so far been conducted to impart a microcirculation property to the aforementioned preparations. Some proposals have been made, including, for example, a method of maintaining a high blood concentration by reducing a size of liposomes in view of relative easiness of a control of physicochemical properties of lipid bilayers of liposomes (Biochimica et Biophysica Acta, Vol. 761, p. 142, 1983), a method of utilizing lecithin having a high phase transfer temperature (Biochemical Pharmacology, Vol. 32, p. 3381, 1983), a method of utilizing sphingomyelin instead of lecithin (Biochemical Pharmacology, Vol. 32, p. 3381, 1983), a method of adding cholesterol as a membrane component of liposomes (Biochimica et Biophysica Acta, Vol. 761, p. 142, 1983) and the like. However, no work based on these methods has been known so far that successfully provides a microparticle drug carrier having favorable retention in blood and being hardly taken up by RES.
As another approach for solution, researches have been made for providing a microcirculation property and escapability from RES by modification of membrane surfaces of liposomes with a glycolipid, glycoprotein, amino acid-lipid, polyethylene glycol-lipid or the like. Substances for the modification so far reported include, for example, glycophorin (The Pharmaceutical Society of Japan, the 106th Annual Meeting, Summaries of Symposia, p. 336, 1986), ganglioside GM1 (FEBS Letters, Vol. 223, p. 42, 1987), phosphatidylinositol (FEBS Letters, Vol. 223, p. 42, 1987), glycophorin and ganglioside GM3 (Japanese Patent Unexamined Publication (Kokai) No. 63-221837), polyethylene glycol derivative (FEBS Letters, Vol. 268, p. 235, 1990), glucuronic acid derivative (Chemical & Pharmaceutical Bulletin, Vol. 38, p. 1633, 1990), glutamic acid derivative (Biochimica et Biophysica Acta, Vol. 1108, p. 257, 1992), polyglycerin phospholipid derivative (Japanese Patent Unexamined Publication No. 6-228012), and the like.
As for modification of liposome surfaces with a polyethylene glycol-lipid, for example, it has been reported that water shell and stability in blood thereof are correlated, and if the water shell is thickened, the stability in blood is increased (Pharm. Tech. Japan, Vol. 12, No. 7, p. 925, 1996). For the purpose of thickening the water shell, an increased amount of added polyethylene glycol-lipid and an increased molecular weight of polyethylene glycol chain are examined. It is considered that, if the amount to be added or the molecular weight is increased as mentioned above, the horizontal three-dimensional spreading of the structure of the polyethylene glycol chain on the surface of a liposome can be suppressed, i.e., changing from a pancake structure to a mushroom structure or further to a brush structure, thereby the structure spreads in the vertical direction to thicken the water shell (Langmuir, Vol. 11, p. 3975). However, it has been reported that if the added amount is increased to become excess, the packing of liposome lipid membrane will be weaker, and the stability of the liposome is degraded (Biophysical Journal, Vol. 74, p. 1371, 1998). Moreover, if the molecular weight of the polyethylene glycol chain is increased, the coagulation point and viscosity become high, and difficulties in handling at an ordinary temperature arise at practical use, for example, inevitable dissolution step of the product.